Adams J W, Sah V P, Henderson S A, Brown J H
Department of Pharmacology, University of California, San Diego, La Jolla 92093-0636, USA.
Circ Res. 1998 Jul 27;83(2):167-78. doi: 10.1161/01.res.83.2.167.
Myocardial infarction results in focal areas of ischemia, hypoxia, necrosis, and decreased contractile function. To compensate for loss of contractile function, remaining viable myocytes undergo hypertrophic growth. Prostaglandin F2alpha (PGF2alpha), which is released from cells of the myocardium during periods of stress such as hypoxia or ischemia/reperfusion, has recently been shown to stimulate hypertrophic growth in neonatal rat ventricular myocytes. In the present study, we determine which growth-related intracellular pathways are required for PGF2alpha to induce morphological and genetic features characteristic of the hypertrophic phenotype. In cardiomyocytes, PGF2alpha increases the hydrolysis of inositol phosphates and induces the translocation of protein kinase C epsilon to the myocyte membrane, consistent with PGF2alpha receptor coupling to Gq. PGF2alpha also activates the extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase pathways. Surprisingly, studies using pharmacological inhibitors and transfection of dominant-interfering proteins demonstrate that PGF2alpha-induced myocyte hypertrophy occurs independent of either PKC, p38, or ERK pathways. Additional studies demonstrate that PGF2alpha stimulates protein tyrosine phosphorylation and activates c-Jun NH2-terminal kinase and suggest that these pathways mediate hypertrophic growth in response to PGF2alpha.
心肌梗死会导致局部区域出现缺血、缺氧、坏死以及收缩功能下降。为了补偿收缩功能的丧失，存活下来的心肌细胞会经历肥大性生长。前列腺素F2α（PGF2α）在诸如缺氧或缺血/再灌注等应激期间从心肌细胞释放，最近已被证明可刺激新生大鼠心室肌细胞的肥大性生长。在本研究中，我们确定PGF2α诱导肥大表型特征性的形态和遗传特征需要哪些与生长相关的细胞内途径。在心肌细胞中，PGF2α增加肌醇磷酸的水解，并诱导蛋白激酶Cε易位至肌细胞膜，这与PGF2α受体与Gq偶联一致。PGF2α还激活细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶途径。令人惊讶的是，使用药理学抑制剂和转染显性干扰蛋白的研究表明，PGF2α诱导的心肌细胞肥大独立于PKC、p38或ERK途径发生。进一步的研究表明，PGF2α刺激蛋白酪氨酸磷酸化并激活c-Jun氨基末端激酶，并表明这些途径介导对PGF2α的肥大性生长反应。
